2-year Studies Research Articles

Efficacy and safety of aquablation of the prostate for patients with symptomatic benign prostatic enlargement: a systematic review.

The aim of this systematic review is to summarize the contemporary literature on aquablation and evaluate its safety and efficacy for the treatment of symptomatic BPE. A systematic search of English language literature was performed using the PubMed-MEDLINE and Web of Science libraries up to 24 July 2019 by combining PICO (patient population, intervention, comparison, and outcome) terms. We retrieved 16 studies, including 446 patients treated with aquablation eligible for data extraction and analysis. Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines were followed. We identified a randomized controlled trial (RCT) comparing aquablation to transurethral resection of the prostate (TURP) with 6-month, 1-year, and 2-year outcomes, three single-center and single-arm studies, three multicenter and single-arm studies, and five subgroup analyses. Aquablation significantly improved International Prostate Symptom Score (IPSS), IPSS-quality of life (IPSS-QoL), maximum urinary flow rate (Qmax) and post void residual (PVR) from baseline to last follow-up in all prospective studies. At 2-year follow-up, aquablation showed non-inferior symptom relief compared to TURP, witha lower risk of anejaculation favoring aquablation and no significant differences regarding Clavien-Dindo events. Although a significant hemoglobin drop was reported in all aquablation single-arm studies and when compared to TURP, it did not translate into increased transfusion rates. Data from the WATER trial demonstrates that aquablation is comparable to TURP in effectively improving symptom scores and functional parameters related to BPE and bladder outlet obstruction. The evidence provided supports the safety of aquablation assessed by procedure-related adverse events.

Testing the Duke Population Health Profile (Duke-PH) in a Sample of Community Health Center Patients.

Introduction: Our purpose was to develop and test a brief, self-report, and scorable survey instrument for measuring population health profiles from the individual respondent's perspective. We defined population health as the state of physical, mental, and social well-being of a group of individuals, including determinants of their well-being.Materials and Methods: Respondents were adult patients in a community health center. Instrument items, an overall scale, and two subscales were developed and evaluated. Reliability was tested by Cronbach's alphas and test-retest correlations; construct validity was tested by correlations between scores and economic and clinical factors; criterion validity was tested by regression analyses for prediction of morbidity and health care utilization by baseline scores; and feasibility was tested by length of administration time.Results: This was a 2-years prospective study of 450 patients, mostly black non-Hispanics (54%) and Hispanics (29%), many with no health insurance (45%), and poor enough to meet the federal poverty level (73%). The Duke Population Health Profile (Duke-PH) was developed with a 14-item PH scale for overall population health profile and two 7-item subscales, one for social determinants and the other for health determinants. Validity of item selection was indicated by item convergent and item discriminant correlations. Scale and subscale reliability were supported for internal consistency by Cronbach's alphas of 0.63–0.73, and for temporal stability by test-retest correlations of 0.65–0.78. Support for construct validity was shown by the more favorable baseline subscale and scale mean scores for patients able to buy private insurance than for patients unable to afford it. Criterion validity was supported by regression analyses showing that baseline scale and subscale scores predicted both baseline morbidity and 6-months utilization. Feasibility was shown by the mean self-administration time of 3.9 min and mean interviewer-administration time of 5.8 min.Discussion: The strength of this study is support for Duke-PH reliability, validity, and feasibility in a community health center patient population. The new instrument is unique because it measures both social and health determinants of population health from the perspective of individuals in the population.

Carcinogenic effect of potassium octatitanate (POT) fibers in the lung and pleura of male Fischer 344 rats after intrapulmonary administration

BackgroundPotassium octatitanate fibers (K2O•8TiO2, POT fibers) are used as an asbestos substitute. Their physical characteristics suggest that respirable POT fibers are likely to be carcinogenic in the lung and pleura. However, previous 2-year inhalation studies reported that respired POT fibers had little or no carcinogenic potential. In the present study ten-week old male F344 rats were left untreated or were administered vehicle, 0.25 or 0.5 mg rutile-type nano TiO2 (r-nTiO2), 0.25 or 0.5 mg POT fibers, or 0.5 mg MWCNT-7 by intra-tracheal intra-pulmonary spraying (TIPS), and then observed for 2 years.ResultsThere were no differences between the r-nTiO2 and control groups. The incidence of bronchiolo-alveolar cell hyperplasia was significantly increased in the groups treated with 0.50 mg POT and 0.50 mg MWCNT-7. The overall incidence of lung tumors, however, was not increased in either the POT or MWCNT-7 treated groups. Notably, the carcinomas that developed in the POT and MWCNT-7 treated rats were accompanied by proliferative fibrous connective tissue while the carcinomas that developed in the untreated rats and the r-nTiO2 treated rats were not (carcinomas did not develop in the vehicle control rats). In addition, the carcinoma that developed in the rat treated with 0.25 mg POT was a squamous cell carcinoma, a tumor that develops spontaneously in about 1 per 1700 rats. The incidence of mesothelial cell hyperplasia was 4/17, 7/16, and 10/14 and the incidence of malignant mesothelioma was 3/17, 1/16, and 2/14 in the 0.25 mg POT, 0.5 mg POT, and MWCNT-7 treated groups, respectively. Neither mesothelial cell hyperplasia nor mesothelioma developed in control rats or the rats treated with r-nTiO2. Since the incidence of spontaneously occurring malignant mesothelioma in rats is extremely low, approximately 1 per 1000 animals (Japan Bioassay Research Center [JBRC] historical control data), the development of multiple malignant mesotheliomas in the POT and MWCNT-7 treated groups was biologically significant.ConclusionThe incidence of pleural mesotheliomas in male F344 rats administered POT fibers and MWCNT-7 was significantly higher than the JBRC historical control data, indicating that the incidence of pleural mesothelioma in the groups administered POT fibers and MWCNT-7 fibers via the airway using TIPS was biologically significant. The incidence of type II epithelial cell hyperplasia and the histology of the carcinomas that developed in the POT treated rats also indicates that respirable POT fibers are highly likely to be carcinogenic in the lungs of male F344 rats.

Increased NK Cell Count in Multiple Sclerosis Patients Treated With Dimethyl Fumarate: A 2-Year Longitudinal Study.

Background: Dimethyl fumarate (DMF) is a disease-modifying drug for relapsing-remitting multiple sclerosis. Among others, DMF impedes immune activation by shifting the balance between inflammatory and regulatory cell types and by inducing apoptosis-triggered lymphopenia. Although the decrease in lymphocyte count is an early effect of the drug in several patients, the long-term impact on lymphocyte subsets is largely unknown.Methods: We performed a 2-years observational study on total lymphocyte count and subsets thereof by flow cytometry of peripheral blood of 38 multiple sclerosis patients in treatment with DMF. Data were collected at the beginning and after 3, 6, 12, and 24 months of therapy.Results: Total lymphocyte count decreased in relation to time of exposure to DMF. Mean absolute B cell count decreased by 34.1% (p < 0.001) within the first 3 months of therapy and then remained stable over time. Mean absolute CD3+ T cells count decrement reached 47.5% after 12 months of treatment (p < 0.001). NK cells count showed a heterogeneous trend, increasing by 85.9% (p < 0.001) after 2 years of treatment. CD4+ T cells and CD8+ T cells substantially decreased, with a significant increase of CD4+/CD8+ ratio during the first year of therapy.Conclusions: NK cells showed a heterogeneous behavior during DMF treatment with a significant increase over time. Since NK cells may also have a regulatory effect on immune system modulation, their increase during DMF treatment might play a role in the efficacy and safety of the drug.

Safety assessment of central nervous system tumors in 2-year rat carcinogenicity studies

Safety assessment of central nervous system tumors in 2-year rat carcinogenicity studies

AhR Activation in Pharmaceutical Development: Applying Liver Gene Expression Biomarker Thresholds to Identify Doses Associated With Tumorigenic Risks in Rats.

Aryl hydrocarbon receptor (AhR) activation is associated with carcinogenicity of non-genotoxic AhR-activating carcinogens such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD), and is often observed with drug candidate molecules in development and raises safety concerns. As downstream effectors of AhR signaling, the expression and activity of Cyp1a1 and Cyp1a2 genes are commonly monitored as evidence of AhR activation to inform carcinogenic risk of compounds in question. However, many marketed drugs and phytochemicals are reported to induce these Cyps modestly and are not associated with dioxin-like toxicity or carcinogenicity. We hypothesized that a threshold of AhR activation needs to be surpassed in a sustained manner in order for the dioxin-like toxicity to manifest, and a simple liver gene expression signature based on Cyp1a1 and Cyp1a2 from a short-term rat study could be used to assess AhR activation strength and differentiate tumorigenic dose levels from non-tumorigenic ones. To test this hypothesis, short-term studies were conducted in Wistar Han rats with 2 AhR-activating carcinogens (TCDD and PCB126) at minimally carcinogenic and noncarcinogenic dose levels, and 3 AhR-activating noncarcinogens (omeprazole, mexiletine, and canagliflozin) at the top doses used in their reported 2-year rat carcinogenicity studies. A threshold of AhR activation was identified in rat liver that separated a meaningful "tumorigenic-strength AhR signal" from a statistically significant AhR activation signal that was not associated with dioxin-like carcinogenicity. These studies also confirmed the importance of the sustainability of AhR activation for carcinogenic potential. A sustained activation of AhR above the threshold could thus be used in early pharmaceutical development to identify dose levels of drug candidates expected to exhibit dioxin-like carcinogenic potential.

Flavonoid Glycosides and Hydroxycinnamic Acid Derivatives in Baby Leaf Rapeseed From White and Yellow Flowering Cultivars With Repeated Harvest in a 2-Years Field Study.

Recently, new annual and biennial cultivars of rapeseed with white flowers have been introduced to the baby leaf market. The white flower trait has been bred into modern cultivars of yellow flowering rapeseed. In baby leaf production, it is common practice to perform several cuts of the same plants, thereby harvesting regrown material. Seven white and yellow flowering annual and biennial rapeseed cultivars were harvested as baby leaves, baby leaf re-growths, and intact plants in order to investigate the content of flavonoid glycosides and hydroxycinnamic acid derivatives. The field experiment was conducted over two consecutive years to obtain seasonal differences. The yields and levels of flavonoid glycosides and hydroxycinnamic acids were higher in 2016 than 2017, due to higher temperatures and radiation. Within the growing stage, the effects of flower color, cultivar, and life cycle on flavonoid glycosides and hydroxycinnamic acids varied; however, in general, life cycle was the main influence that resulted in elevated levels of flavonoid glycosides and hydroxycinnamic acids in biennial cultivars, compared to annual cultivars. The effects of the growing stage differed between years, and were influenced by climatic conditions. In conclusion, the choice of life cycle (annual or biennial cultivars) and seasonal effects was of major influence, overruling the effect of developmental stage on the content of flavonoid glycosides and hydroxycinnamic acids.

Effect of cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis

BackgroundImmune reconstitution therapies (IRT) for patients with multiple sclerosis are used for short, intermittent treatment periods to induce immune resetting and allow subsequent treatment-free periods. Cladribine tablets are postulated to be an IRT that causes selective and transient reductions in CD19+ B cells and T cells, followed by reconstitution of adaptive immune function. ObjectiveTo characterize long-term lymphocyte count changes in pooled data from the 2-year CLARITY and subsequent 2-year CLARITY Extension studies, and the PREMIERE registry (Long-term CLARITY cohort). MethodsData from patients randomized to placebo (n = 435) or cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg; n = 685) in CLARITY or CLARITY Extension, including time spent in the PREMIERE registry were pooled to provide long-term follow-up data. The study investigated absolute lymphocyte counts (ALC) up to 312 weeks and B and T cell subsets up to 240 weeks after the first dose, in patients receiving placebo or cladribine tablets 3.5 mg/kg administered as two short (4 or 5 days) weekly treatments at the start of months 1 and 2 in each treatment year, followed by no further active treatment. ResultsTreatment with cladribine tablets 3.5 mg/kg resulted in selective reductions in B and T lymphocytes. Lymphocyte recovery began soon after treatment in each of years 1 and 2. Median ALC recovered to the normal range and CD19+ B cells recovered to threshold values by week 84, approximately 30 weeks after the last dose of cladribine tablets in year 2. Median CD4+ T cell counts recovered to threshold values by week 96 (approximately 43 weeks after the last dose of cladribine tablets in year 2). Median CD8+ cell counts never dropped below the threshold value. ConclusionThese results show the dynamics of lymphocyte count changes following treatment with cladribine tablets 3.5 mg/kg. The immune cell repopulation results provide further evidence that cladribine tablets may represent a form of IRT.

Central nervous system tumors in 2-year rat carcinogenicity studies: perspectives on human risk assessment.

Rodent in vivo carcinogenicity bioassays are required for human risk assessment and have been utilized in this capacity for decades. Accordingly, there is an abundance of data that could be accessed and analyzed to better understand the translatability of xenobiotic-induced rodent tumors to human risk assessment. In the past decade, various groups have published assessments of the value garnered by these life-time rodent studies. Results and recommendations from the International Council for Harmonization Expert Working Group (ICH-S1 EWG) on the predictability of the current testing paradigm and proposal for an integrated approach to human carcinogenicity risk assessment are pending. Central nervous system (CNS) tumors in rats are rare and translatability to human remains unknown. This review focuses on microglial cell tumors (MCT) of the CNS in rats including its classification, nomenclature, incidence and translatability to human risk assessment. Based on emerging immunohistochemistry (IHC) characterization, glial tumors previously thought of astrocytic origin are more likely MCTs. These may be considered rodent specific and glucose dysregulation may be one component contributing to their formation. Based on review of the literature, MCTs are rarely diagnosed in humans, thus this tumor type may be rat-specific. We propose to include MCTs as a tumor type in revised International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) classification and all glial tumors to be classified as MCTs unless proven otherwise by IHC.

Concomitent Chemotherapy and radiotherapy in patients with Locally Advanced Rectal Carcinoma

Introduction:In recent years, the approach to adjuvant therapy for rectal cancer in the United States and Europe has been shifting toward preoperative therapy to promote sphincter-preserving surgery and decrease acute and late bowel toxicity. Patients&Methods:This study will be a phase II trial to study the effectiveness of combining chemotherapy (Gemcitabine) and external – beam radiotherapy followed by surgery in treating patients who have locally advanced rectal cancer , It is carried on Sohag University Hospital & Sohag NCI since( October 2014- December2017),the dose of radiotherapy 5040 cGy /28ttt,and chemotherapy dose is 45mg/m2 given twice weekly during radiotherapy sessions only, the study included 30 patients (age 18 and over), having rectal cancer with the following eligibility criteria:histologically proven ,previously untreated rectal carcinoma , every patient in the study was subjected to the following:history & physical examination,laboratory investigations, radiological studies. Results:Thirty patients were included in the study,13 females (43.3%) and 17 male( 56.6%) mean of the age was 49 years. (range24-65year), most of them had adenocarcinoma of the rectum, the main presenting symptom was bleeding per rectum(56.7%), as regard to the response to the neoadjuvant treatmen 12/30 patients (40%) achieved Partial response, 8/30patients(27.6%) achieved complete response and 10/30 patients (33%) had no response, abdomino - perineal resection was performed in 19 patients(63.3%) and 11 patients (36.7%) underwent sphincter preservation operation, about the toxicity in this study,for chemotherapy diarrhea was the most common manifestation which seen in 25 patients(83%),followed by loss of appetite seen in 9 patients(63.3%), for radiotherapy 19 patients (63%) developed wet desquamation. the rate of Overall Survival of the 2-years study is (80%),the Disease free survival is (63%)while the progression free survival is (72%),N stage was the only significant factor affecting the disease free survival and overall survival. Conclusion: Pre-operative chemo-radiotherapy in dose and fractionation schedule used is safe, effective and well tolerated, allowed sphincter preservation which performed in (36.7%) of patients

Histopathology re-examination of the NTP toxicity/carcinogenicity studies of tert-butyl alcohol to identify renal tumor and toxicity modes of action

Tert-butyl alcohol (TBA) targets the rat kidney following repeated exposures, including renal tubule tumors. The mode of action (MOA) of these tumors, concluded by a pathology working group, involves both alpha2u-globulin nephropathy (α2u-gN) and exacerbated chronic progressive nephropathy (CPN), but has been disputed and an undefined MOA proposed. This study further reviews the histology slides of male and female rat kidneys from the NTP drinking water 13-week toxicity and 2-year carcinogenicity studies, including the 15-month interim sacrifice group. The papillary epithelial lining alteration formerly referred to as “transitional cell hyperplasia” develops as part of advanced CPN and does not represent a separate toxicity. No changes were observed in the kidney pelvis urothelium. The only alterations in subchronic male rats involved α2u-gN and CPN, without test article-related alterations in females. Focused examination of areas of parenchyma unaffected by CPN in TBA-treated male and female rats of the chronic studies revealed no renal tubule abnormalities other than from the effects of α2u-gN and CPN. Unrelated to toxicity were spontaneous amphophilic or vacuolar tubule proliferative lesions. All observed TBA-associated non-neoplastic and neoplastic histopathological changes in the kidney can be explained by α2u-gN or enhanced CPN, neither of which are relevant to humans.

Absence of Plasma Gastric Biomarker Elevations with Chronic Dosing of Avatrombopag, a Novel Oral Thrombopoietin Receptor Agonist, in Patients with Chronic Immune Thrombocytopenia in Phase 3 Trials

Background: Avatrombopag (AVA) is an oral, thrombopoietin receptor agonist approved by FDA for the treatment of thrombocytopenia in patients with chronic liver disease scheduled to undergo a procedure. AVA is also being developed for other indications including chronic immune thrombocytopenia (cITP) (Bussel et al, Blood, 2014; Wojciech et al, Br J Haematol, in press 2018). In repeated-dose studies in mice, rats and cynomolgus monkeys, there were AVA dose, concentration, and duration-dependent histologic changes in gastric fundic glands that reversed by 4 weeks after dosing was stopped. This was associated with decreased gastric acid production, hypergastrinemia, and increased intragastric pH in all species. The NOAEL in 2-year toxicology studies was defined at exposures 4 to 21-fold the recommended human AVA dose.Hypergastrinemia and parietal cell hyperplasia have also been reported with proton pump inhibitors (PPIs) and H2-receptor antagonists (H2RA). These findings may be secondary to suppression of gastric acid production, and, in rodents, may lead to gastric carcinoids. Findings of hypergastrinemia-related gastric hyperplasia in rodents have a low risk/relevance to humans.To further evaluate the preclinical findings and screen for atrophic gastritis, gastric biomarkers (gastrin, gastrin-17, and pepsinogen I/II [PG-I/PG-II]) were measured in 2 Phase 3 trials with chronic AVA dosing. These multicenter, randomized, controlled Phase 3 trials were conducted in patients with cITP, and assessed clinical safety and efficacy of AVA versus placebo (PBO) (Study 1- NCT01438840) or eltrombopag (ELT) (Study 2- NCT01433978); Study 2 was terminated early due to enrollment challenges.Methods: Both Phase 3 trials enrolled adults (≥18 years) with chronic ITP (Baseline platelet count (PC) <30x109/L), who were randomized 2:1 to receive either 20 mg/day AVA or PBO (Study 1) or 1:1 to 20 mg/day AVA or ELT (50 mg/day) (Study 2) orally with food for 26 weeks. Individual patient AVA (5-40 mg/day) or ELT (25-75 mg/day) dose titration was permitted.Patients with Baseline fasting gastrin-17 levels greater than upper limit of normal (ULN) were excluded from the study, as were patients taking PPIs or H2RAs if not on a stable dose or if gastrin-17 levels were >1.5 times the ULN.Safety analyses included adverse event (AE) monitoring and laboratory testing, including fasting gastric biomarkers. Patients who developed 2 consecutive fasting gastrin-17 levels >2.5 times the ULN or low serum PG-I levels or low PG-I/PG-II ratio (with low fasting gastrin-17 levels) were to be discontinued from the trials. Patients with elevations >5 times the ULN were to undergo endoscopy to assess the gastric mucosa.Results: A total of 64 patients were treated with AVA across the two trials (Study 1 n=47; Study 2 n=17); the majority were white (92.2%) and female (64.1%), with a mean age of 46.6 years. The median duration of exposure to AVA was 35.1 weeks, with a mean daily dose of 24.6 mg; 75% of subjects received AVA doses between 5 and 40 mg for ≥20 weeks. AVA was shown to be superior to PBO in the median cumulative number of weeks of platelet response (PC ≥50×109/L in the absence of rescue therapy) in Study 1 (12.4 vs. 0.0 weeks, respectively; p <0.0001). Mean Baseline PCs in Study 1 were similar in AVA- and PBO-treated subjects (14.1 and 12.7x109/L, respectively), and peaked at 205.4 and 11.6x109/L on Week 2; mean Baseline PCs were lower in Study 2 in AVA- compared to ELT-treated subjects (13.0 and 18.2x109/L, respectively), and increased to 184.8 and 91.6x109/L at Week 2.Of the AVA-treated patients, no significant changes in the mean fasting gastrin, gastrin-17, PG-I, PG-II, or the PG-I/PG-II ratio were observed from Baseline over the course of the trial (Figure 1). In addition, no patients met the gastric biomarker change criteria for discontinuation or to undergo endoscopy. Common AEs in Study 1 included headache, contusion and upper respiratory tract infections, with 4 cases of thromboembolic events.Conclusions: In Phase 3 trials, AVA was shown to be effective and well tolerated in the treatment of thrombocytopenia in patients with cITP, with most patients demonstrating substantial platelet increases. In particular, treatment of cITP with AVA was not associated with an increase in gastric biomarkers including gastrin, gastrin-17 or pepsinogen and, therefore, no signal of gastric toxicity was identified with chronic AVA dosing of up to 26 weeks. [Display omitted] DisclosuresBussel:Prophylix: Consultancy, Research Funding; Protalex: Consultancy; Amgen Inc.: Consultancy, Research Funding; Uptodate: Honoraria; Rigel: Consultancy, Research Funding; Momenta: Consultancy; Novartis: Consultancy, Research Funding. Allen:Dova Pharmaceuticals: Employment, Equity Ownership. Tian:Dova Pharmaceuticals: Employment, Equity Ownership. Kuter:Pfizer: Consultancy; ONO: Consultancy; Amgen Inc.: Consultancy; Novartis: Consultancy; Syntimmune: Consultancy; Protalex: Research Funding; Rigel: Consultancy, Research Funding; Argenx: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Consultancy, Research Funding; BMS: Research Funding; Principia: Research Funding.

Beyond the Walls: An Evaluation of a Pre-Release Planning (PReP) Programme for Sentenced Mentally Disordered Offenders.

Background: Prison mental health services have tended to focus on improving the quality of care provided to mentally disordered offenders at the initial point of contact with the prison system and within the prison environment itself. When these individuals reach the end of their sentence and return to the community, there is an increased risk of morbidity, mortality, homelessness and re-imprisonment. New models of care have been developed to minimize these risks.Objectives: The objective of this project was to establish a Pre-Release Planning (PReP) Programme with social work expertise, to enhance interagency collaboration and improve continuity of care for mentally disordered offenders upon their release. We aimed to evaluate the first 2 years of the programme by measuring its success at improving the level of mental health support and the security and quality of accommodation achieved by participants upon release in comparison to that reported at time of imprisonment. Additionally, we aimed to explore the impact of these outcomes on rates of re-imprisonment.Methods: A process of participatory action research was used to develop and evaluate the first 2 years of the programme. This was a naturalistic prospective observational whole cohort study.Results: The PReP Programme supported 43 mentally disordered offenders, representing 13.7%, (43/313) of all new assessments by the prison's inreach mental health service during the 2 years study period. When compared with that reported at time of reception at the prison, gains were achieved in level of mental health support (FET p < 0.001) and security and quality of accommodation (FET p < 0.001) upon release. Of those participants seen by the PReP Programme, 20 (46.5%, 20/43) were returned to prison during the 2-years study period. There was no significant relationship between re-imprisonment and gains made in mental health support (FET p = 0.23) or accommodation (FET p = 0.23).Conclusions: We have shown that compared to that reported at time of reception at prison, the level of mental health support and the security of tenure and quality of accommodation both improved upon release following the intervention of the programme. Improved mental health support and accommodation were not associated with lower rates of re-imprisonment.

Endoscopic Ultrasound Elastography for Evaluation of Lymph Nodes: A Single Center Experience.

Background and Aim The differentiation between malignant and benign lymph nodes (LNs) is important for tumor staging, for detection of prognosis, and for selection of the best treatment strategy in many cancers. On B-mode EUS, there are some known criteria that suggest the malignant nature of LNs; these criteria may be found in benign LNs. The aim of the work is to evaluate the effectiveness of elasticity score and SR to differentiate between benign and malignant LNs. Patients and Methods The study was designed as a retrospective study that included 40 patients with abdominal or mediastinal LNs, either associated with primary masses or isolated, referred for EUS evaluation. Elasticity scores and SR were determined during the examination and finally, EUS-FNA was done at the end of the procedure. Results In this 2-years study, 40 patients were enrolled (24 malignant; 16 benign). There were 23 males and 17 females. Their mean age was 52.5 years (range: 28–77). ES alone had a specificity of 87.5%, sensitivity of 41.7%, PPV of 83.3%, NPV of 50%, and accuracy of 60%. Based on the ROC curve analysis results, the best cut-off level of SR to obtain the maximum area under the curve (AUC) was 6.7 with a specificity of 99.9%, sensitivity of 57.1%, PPV of 99.9%, NPV of 64%, and accuracy of 77.5%. Conclusion The use of elasticity score and SR increases the reliability of differentiation between benign and malignant LNs and can decrease the number of unnecessary biopsies.

Water productivity, growth, and physiological assessment of deficit irrigated cotton on hyperarid desert-oases in northwest China

Critical water shortage and hyperaridity are the principal reasons, limiting cotton cultivation on desert-oases in northwest China. However, if water dearth is effectively managed then these terrains can also add significant contribution in regional and country’s total cotton production due to favorable climate. In that perspective, a 2-years (2015–2016) field study was conducted on cultivable southern periphery of Taklamakan desert to optimize water productivity of deficit drip irrigated cotton through evaluating its water use (ETc), growth, and physiology based water relations. Treatments included four drip irrigation regimes based on 100 (D100), 80 (D80), 60 (D60), and 40% (D40) replenishment of depleted water from field capacity. Results revealed that average ETc ranged from 510 mm at 40% to 1079 mm at 100% water replenishment. Crop growth and pre-dawn leaf water potential (ψpd) successively declined with reducing irrigation amount. Photosynthesis (A), and stomatal conductance (gs) of D80 plants decreased by 15% at squaring and by only 8% at later stages while, this decline was more vigorous under 60 and 40% water replenishments. The 80% irrigated plants resulted in only 13% yield reduction from D100 whereas, the average seed cotton yield varied from 2433 kg ha−1 in 40% to 4376 kg ha−1 under 100% water replenishment. The maximum irrigation, and crop water use efficiencies (IWUE, WUE) were recorded 0.62 and, 0.48 kg m−3, respectively, which reduced with increasing irrigation amounts. In addition, crop growth and physiological attributes showed linear correlations with ETc and irrigation regimes during yield formation. Following economic evaluation, these results suggested that, irrigating cotton up to 80% field capacity would provide the optimum yield and net income with 20% water saving while, D60 could save 40% water but, subject to major yield and profit loss. However, if water is sufficiently available then 100% irrigation can be practiced for maximizing cotton productivity and net gains on desert-oases.

MRI analysis of peripheral soft tissue composition, not body mass index, correlates with outcomes following anterior cruciate ligament reconstruction

To utilize MRI to assess the relationship between BMI, peripheral soft tissue composition about the knee, and surgical outcomes in patients undergoing primary ACL reconstruction. It was hypothesized that a fatty periarticular soft tissue composition may be better than BMI at predicting poor outcomes after ACL reconstruction. Fifty-eight patients who underwent primary acute ACL reconstruction were identified from the surgical database and their data were retrospectively reviewed. Patients were selected based on availability of 2-year IKDC outcome scores, BMI data, and preoperative MRI studies. To approximate peripheral soft tissue composition, novel measurements of axial MRI images were employed using PACS ROI measurement tool. Relationships were assessed between IKDC outcome scores and measures of body habitus including BMI, total knee area, knee fatty-connective tissue area, and fatty-connective tissue to bone size ratio. The median BMI was 24.3kg/m2 (range 18.5-36.9). Median IKDC score was 81.0 (range 46-100). BMI was correlated with total knee area (R = 0.72) and periarticular fat (R = 0.53). Neither continuous BMI (n.s.) nor total knee area (n.s.) was predictor of IKDC outcomes scores. Periarticular fatty-connective tissue trended towards predicting negative outcomes (n.s.). Periarticular fatty-connective tissue to bone size ratio was a significant negative predictor of IKDC scores (p = 0.03). Patients with more fat than bone on axial MRI (ratio > 1, N = 34) reported a lower mean IKDC score compared to patients with a ratio < 1 (N = 24) (77.2 vs. 87.7, p = 0.0028). The top quartile (N = 14) of these ratios reported a mean IKDC score of 68.9, compared to 87.3 of the bottom quartile (p = 0.0001). Periarticular soft tissue composition, as approximated by the novel MRI analysis of this study, is a better predictor of outcomes following ACL reconstruction than is BMI. This information can be utilized in guiding surgeon and patient expectations following surgery, either via a direct application of these measurements or heightened awareness of the importance of peripheral body habitus. III.

ПРОДУКТИВНОСТЬ ПШЕНИЦЫ ПОЛБЫ СОРТА РУНО ПРИ РАЗЛИЧНЫХ УРОВНЯХ МИНЕРАЛЬНОГО ПИТАНИЯ, НОРМЫ ВЫСЕВА И ГЛУБИНЫ ЗАДЕЛКИ СЕМЯН В УСЛОВИЯХ ПРЕДКАМСКОЙ ЗОНЫ РЕСПУБЛИКИ ТАТАРСТАН

The article presents the results of 2-year studies on the main agrotechnical methods for cultivating spring wheat polba in specific conditions. It is shown that the main agrotechnological method, that determines the productivity of a variety, is the introduction of calculated doses of mineral fertilizers, the depth of seeding. To a large extent, the productivity is associated with a combination of nutritional levels, optimal stalk density and depth of seeding. The most effective variants of cultivation technology are established. Changes in the formation of the density of stemstock are revealed with a change in the seeding rates, the depth of seeding at both feeding levels.

Tumor site concordance and genetic toxicology test correlations in NTP 2-year gavage, drinking water, dermal, and intraperitoneal injection studies

The National Toxicology Program has conducted 594, 2-year studies exposing various strains of rats and mice via different routes of exposure. In the current study, we analyze the results from 108 chemicals tested in 106, 2-year studies conducted by exposing F334/N rats and B6C3F1 mice via gavage. An additional 18, 2-year gavage studies have been conducted in Osborne–Mendel rats and B6C3F1 mice on 19 different chemicals. We analyze the results from 23 chemicals tested in 21, 2-year studies conducted by exposing F334/N rats and B6C3F1 mice via drinking water; 18 chemicals tested in 18, 2-year studies conducted by exposing F334/N rats and B6C3F1 mice via dermal application; and 11 chemicals tested in 11, 2-year studies conducted by exposing F334/N rats and B6C3F1 mice via intraperitoneal injection. The results from these 174 studies are analyzed and discussed separately. The neoplasticity of each chemical was analyzed for tumor incidence by species–sex category, tumor site concordance across species, and tumor site concordance across sex within species. When available the Ames Salmonella mutagenicity assay results, and any results from a test for genotoxicity other than the Ames test, were correlated with the neoplasticity results. Tumor site concordance across sex within species is generally higher than tumor site concordance across species. In addition, the high degree of variability of Ames test results suggests that historical Ames test data are less reliable than recent results conducted under good laboratory practices and employing Organization for Economic Cooperation and Development protocols relevant to the physicochemical characteristics of the test chemical.

Ames mutagenicity, structural alerts of carcinogenicity, Hansch QSAR parameters (ClogP, CMR, MgVol), tumor site concordance/multiplicity, and tumorigenicity rank in NTP 2-year rodent studies

Since its inception in 1976, the National Toxicology Program (NTP) has conducted 594 2-year studies on rats and mice by a number of routes of administration including inhalation, feed, drinking water, dermal, and intraperitoneal injection. Of these studies, the results on 470 chemicals were of adequate technical quality to be incorporated into final technical reports. In this study, the 470 chemicals were categorized from 1 to 48 by the level of “clear” neoplastic evidence in male and female rats, and in male and female mice, and given an ordinal rank from 1 to 135 following additional considerations regarding tumor site concordance and tumor multiplicity. The resultant tumorigenicity category score and ordinal rank score were examined for associations with results in the Ames Salmonella mutagenicity assay; presence or absence of structural alerts of carcinogenicity; and three Hansch Quantitative Structure-Activity Relationship (QSAR) parameters, namely, calculated base 10 logarithm of the octanol–water partition coefficient (ClogP), calculated molar refractivity (CMR), and McGowan molecular volume (MgVol). Smaller molecular volumes were found to be associated with higher levels of tumorigenicity. Whereas lower rather than higher levels of lipophilicity were found to be associated with higher levels of tumorigenicity. Positive Ames test results were positively correlated with overall tumorigenicity and with possession of structural alerts. Since larger organic molecules have more chemical reaction centers, it was not surprising that higher ClogP values were positively correlated with the number of structural alerts. The results from this study demonstrate the ability to devise rational rules for relative tumorigenicity that correlate, in biologically plausible ways, with known parameters of toxicity.

Bronchioloalveolar lung tumors induced in “mice only” by non-genotoxic chemicals are not useful for quantitative assessment of pulmonary adenocarcinoma risk in humans

Chemicals classified as known human carcinogens by International Agency for Research on Cancer (IARC) show a low level of concordance between rodents and humans for induction of pulmonary carcinoma. Rats and mice exposed via inhalation for 2 years show a low level of concordance in both tumor development and organ site location. In 2-year inhalation studies using rats and mice, when pulmonary tumors are seen in only male or female mice or both, but not in either sex of rat, there is a high probability that the murine pulmonary tumor has been produced via Clara cell or club cell (CC) metabolism of the inhaled chemical to a cytotoxic metabolite. Cytotoxicity-induced mitogenesis increases mutagenesis via amplification of the background mutation rate. If the chemical being tested is also negative in the Ames Salmonella mutagenicity assay, and only mouse pulmonary tumors are induced, the probability that this pulmonary tumor is not relevant to human lung cancer risk goes even higher. Mice have a larger percentage of CCs in their distal airways than rats, and a much larger percentage than in humans. The CCs of mice have a much higher concentration of metabolic enzymes capable of metabolizing xenobiotics than CCs in either rats or humans. A principal threat to validity of extrapolating from the murine model lies in the unique capacity of murine CCs to metabolize a significant spectrum of xenobiotics which in turn produces toxicants not seen in rat or human pulmonary pathophysiology.